A new preprint study suggests that transplanted hearts’ epigenetic age and possibly function are influenced by their recipients’ age. The findings can be relevant to both expanding the donor pool and rejuvenation through organ replacement [1].
The heart of the matter
Over the last few decades, organ transplantation has revolutionized treatment of multiple conditions. It is also one of the most promising “corner-cutting” anti-aging strategies: why understand and learn how to alter the insanely complex biology of aging when we can simply replace organs with brand-new spare parts?
Unfortunately, organ availability remains a major bottleneck. In recent years, the demand for organ transplants has grown considerably, in part due to population aging, while supply has failed to keep up. Growing organs in genetically modified animals is a challenging but promising route [2]. However, until this happens on a large scale, human organs remain the only source.
For organs such as the heart, younger donors are generally preferred, although hearts from older but particularly healthy donors are sometimes used. However, previous research suggests that younger tissues transplanted into older bodies can acquire older molecular profiles, and vice versa. A new study from Harvard, published as a preprint and not yet peer-reviewed, provides an intriguing and potentially valuable insight into this phenomenon.
The recipient’s age matters, the heart’s age is less important
First, the researchers transplanted hearts between young, middle-aged, and old mice, while leaving each recipient’s own heart in place. This design connected the graft to the recipient’s circulation while also retaining the native heart for comparison. The mice belonged to the same inbred strain, C57BL/6, to minimize the immune reaction against genetically foreign tissue.
Four to six months later, the researchers collected the graft, native heart, liver, and blood and used three epigenetic clocks to estimate their biological ages. All three showed that the transplanted heart’s biological age shifted toward the recipient’s age: young hearts developed older-looking methylation patterns in older mice, while old hearts showed younger-looking patterns in younger mice. This suggests that the body’s environment can alter aspects of a heart’s biological aging.
“The most striking finding is how strongly the age of the recipient influences the biological age of the transplanted heart,” Vadim Gladyshev, a professor of medicine at Harvard Medical School and a corresponding author of the study, told Lifespan News. “An old heart placed into a young organism becomes molecularly younger, while a young heart placed into an old organism moves in the opposite direction. This tells us that the biological age of an organ is shaped by the systemic environment in which it resides.”
Having found that the recipient’s age influences the graft, the authors tested the reverse. They measured the epigenetic ages of the recipients’ native heart, liver, and blood and found no consistent effect. Thus, at least in this experimental setting, the body had a much clearer effect on the transplanted heart than vice versa.
The authors next examined the transcriptome, comparing gene expression patterns with previously established signatures of normal aging and of lifespan-extending interventions. RNA sequencing showed substantial gene expression changes: young grafts in old recipients shifted toward aging-associated expression patterns, while old grafts in young recipients shifted toward patterns associated with longevity interventions.
The strongest findings involved mitochondrial processes: these energy-related gene programs were downregulated in young hearts transplanted into old bodies and upregulated in old hearts transplanted into young bodies, relative to hearts from donors transplanted into age-matched recipients.
The researchers then went beyond mice and examined human heart transplants using a hospital dataset of 407 transplantations between 2002 and 2022. For the molecular analysis, the researchers took archived heart-muscle biopsies from just 11 recipients. Five had received hearts from older donors, while six had received hearts from younger donors.
Using methylation clocks, they calculated age deviation: clock-estimated age minus donor chronological age. Two of three clocks found significant differences between the older-to-younger and younger-to-older transplant groups. The third moved in the same direction but failed to reach statistical significance.
“What I like about this study is that it straddles both the fundamental biology of aging and its clinical translation,” said Jesse Poganik, an instructor in medicine at Harvard Medical School and a co-first author of the study. “On the one hand, we discovered a phenomenon that we termed biological age assimilation, that appears to be a fundamental and general principle of biological aging. On the other hand, the idea that older organs assimilate the biological age of younger recipients has important potential implications for transplant medicine, including efforts to reduce the organ donor shortage.”
Human data points in the same direction
The researchers also examined clinical records from hundreds of patients about one year after heart transplantation. After accounting for donor age and recipient sex, older recipients had higher heart rates, thinner posterior walls of the heart’s main pumping chamber, and lower exercise capacity, although the proportion of blood pumped out with each beat was not significantly associated with recipient age. These results are consistent with the idea that the recipient’s environment influences the transplanted heart’s condition and performance. However, differences in health, medications, and exercise habits could also help explain the results, and exercise capacity depends on more than the heart.
“For transplantation, this raises the possibility that older donor organs may be more useful than we currently assume,” said Gladyshev, “although we still need to understand long-term outcomes and the effects of irreversible structural damage.”
While old hearts being rejuvenated by younger bodies suggests a possibility of expanding the donor pool with older donors, there is the flip side of the coin: younger hearts acquiring older molecular profiles in older bodies raises the question of how long the rejuvenating effects of organ replacement can last without also rejuvenating the rest of the body.
“The immediate question these findings raise is on the viability of tissue/cell type targeted aging therapeutics,” said Poganik. “If we have a way to rejuvenate a heart, does it assimilate to the age of the old host months-years later? I think this is an important question for the future. Possible implications are that focus should be on systemic interventions, or perhaps we need to identify targeted interventions that can outpace the biological age assimilation effects (should such interventions exist).”
“What I find most interesting here is that the effect goes both ways: not only do old recipients ‘re-age’ young hearts, but young recipients seem to rejuvenate old hearts, at least to some degree,” said Yuri Deigin, CEO of the cellular reprogramming startup YouthBio, who was not involved in this study. “To me, that is a pretty strong indication that biological age is not just a passive record of how much local damage a tissue has accumulated. At least part of it looks like an actively maintained state that the rest of the organism keeps imposing on its tissues. This matters a lot for organ replacement. If you put a young organ into an old body, it seems the body will simply start teaching that organ to be old. Conversely, an older organ placed into a younger body may have much more capacity for rejuvenation than we usually assume.”
Literature
[1] Poganik, J. R., Matsunaga, T., Tyshkovskiy, A., Lu, A., Haghani, A., Zhou, H., … & Gladyshev, V. N. (2026). Transplanted hearts assimilate the recipient’s biological age. bioRxiv, 2026-09.
[2] Anand, R. P., Layer, J. V., Heja, D., Hirose, T., Lassiter, G., Firl, D. J., … & Qin, W. (2023). Design and testing of a humanized porcine donor for xenotransplantation. Nature, 622(7982), 393-401.
[3] Ding, R., Chen, X., Wu, D., Wei, R., Hong, Q., Shi, S., … & Xie, Y. (2013). Effects of aging on kidney graft function, oxidative stress and gene expression after kidney transplantation. PLoS One, 8(6), e65613.
View the article at lifespan.io
